Abstract
Purpose
5-chloro-2,4-dihydroxypyridine (gimeracil) is a component of the oral fluoropyrimidine derivative S-1. Gimeracil was originally added to S-1 to yield prolonged 5-fluorouracil (5-FU) concentrations in serum and tumor tissues by inhibiting dihydropyrimidine dehydrogenase, which degrades 5-FU. We previously demonstrated that gimeracil enhances the efficacy of radiotherapy through the suppression of homologous recombination (HR) in DNA double strand repair. The goal of this paper was to examine the effects of gimeracil on the sensitivity of anticancer drugs and hyperthermia in order to obtain effective radiosensitization.
Materials and methods
Various cell lines, including DLD 1 (human colon carcinoma cells) and cells deficient in HR or nonhomologous end-joining (NHEJ), were used in clonogenic assays. The survival of these cells after various treatments (e.g., drug treatment, heat treatment, and radiation) was determined based on their colony-forming ability.
Results
Gimeracil enhanced cell-killing effects of camptothecin (CPT), 5-FU, and hydroxyurea. Gimeracil sensitized effects of CPT or 5-FU to cells deficient in HR or NHEJ to a similar extent as in other cells (DLD1 and a parent cell), indicating that its sensitizing mechanisms may be different from inhibition of HR or NHEJ. Combination of gimeracil and CPT or 5-FU sensitized radiation more effectively than each modality alone. Gimeracil also enhanced heat sensitivity at 42°C or more. The degree of heat sensitization with gimeracil increased as the temperature increased, and the combination of gimeracil and heat-sensitized radiation was more effective than each modality alone.
Conclusion
Gimeracil enhanced sensitivity of CPT, 5-FU, and hyperthermia. Combination of these modalities sensitized radiation more efficiently than each modality alone.
Zusammenfassung
Ziel
5-Chlor-2,4-Dihydroxypyridin (Gimeracil) ist eine Komponente des oralen Fluoropyrimidin-Derivats S-1. Gimeracil wird ursprünglich zu S-1 hinzugefügt, um die 5-FU-Konzentrationen in Blutserum und Tumorgewebe länger aufrechtzuerhalten. Dies beruht auf einer Hemmung der Dihydropyrimidin-Dehydrogenase, die 5-FU abbaut. In früheren Untersuchungen konnten wir zeigen, dass Gimeracil die Wirksamkeit der Strahlentherapie durch Unterdrückung der homologen Rekombination (HR) bei der Reparatur von DNA-Doppelstrangbrüchen verbessert. Im vorliegenden Beitrag haben wir die Wirkung von Gimeracil auf die Empfindlichkeit gegenüber Chemotherapeutika und Hyperthermie untersucht, um eine effektive Strahlensensibilisierung zu erzielen.
Material und Methodik
Wir benutzten verschiedene Zelllinien einschließlich DLD-1 (humane Kolonkarzinomzellen) und Zellen mit HR- bzw. einer NHEJ (nichthomologen Endverknüpfung)-Defizienz in klonogenen Tests. Das Überleben dieser Zellen wurde nach verschiedenen Behandlungen wie medikamentöser Behandlung, Wärmebehandlung und Bestrahlung anhand der Koloniebildungsfähigkeit bestimmt.
Ergebnisse
Gimeracil verstärkte die zelltötende Wirkung von Camptothecin (CPT), 5-Fluorouracil (5-FU) und Hydroxyurea. In HR- bzw. NHEJ-defizienten Zellen verstärkte Gimeracil die zelltötende Wirkung von CPT und 5-FU im gleichen Maß wie in anderen Zellen (DLD-1 und Elternzellen). Dies deutet darauf hin, dass hier andere sensibilisierende Mechanismen als bei der Hemmung von HR oder NHEJ zum Tragen kommen. Der kombinierte Einsatz von Gimeracil und CPT bzw. 5-FU bei der Strahlentherapie führte zu einer wirksameren Strahlensensibilisierung als jede Behandlungsmodalität für sich allein. Gimeracil erhöhte auch die Wärmeempfindlichkeit bei Temperaturen ab 42°C. Der Grad der Wärmeempfindlichkeit unter Gimeracil stieg mit zunehmenden Temperaturen. Die Kombination von Gimeracil mit Wärme über 42°C führte zu einer stärkeren Strahlensensibilisierung als jede einzelne Behandlungsmodalität für sich allein.
Schlussfolgerung
Gimeracil erhöhte die Empfindlichkeit für CPT, 5-FU und Hyperthermie. Eine Kombination dieser Modalitäten sensibilisiert für Strahlung effizienter als jede Modalität allein.
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Conflict of interest
The corresponding author states the following: potential conflicts of interest exist. One of the authors (Dr. M. Fukushima) is an employee of Taiho Pharmaceutical Co., Ltd. Gimeracil was supplied by Taiho Pharmaceutical Co., Ltd.
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Takagi, M., Sakata, K., Someya, M. et al. The combination of hyperthermia or chemotherapy with gimeracil for effective radiosensitization. Strahlenther Onkol 188, 255–261 (2012). https://doi.org/10.1007/s00066-011-0043-6
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DOI: https://doi.org/10.1007/s00066-011-0043-6